The measurement of biomedical compounds in complex matrices with electrospray mass spectrometry can be significantly improved by increasing the ionization efficiency and decreasing the effects of matrix components on the analytical signal (sometimes referred to as matrix suppression). The objective of these studies is to demonstrate the enhancement of analytical utility of electrospray by incorporating a novel technique, described as counter-ion impingement electrospray (CII.ES), to increase the sensitivity of electrosprayed analytes by at least one order of magnitude, as well as, reduce the deleterious effects of other sample components on the analytical response. We will demonstrate the feasibility of using counter-ion impingement as a control method for generation of ions with electrospray. Subsequently, we will evaluate the practical operating regime of CII-ES in order to establish the boundaries, limitations, and operating utility of the proposed technology. The final objective of Phase I will be to demonstrate the analytical utility of CII- ES on applications with both singly and multiply charged molecules, and ligand bound species. PROPOSED COMMERCIAL APPLICATIONS: Currently, LC/MS/(MS) is estimated at $300-400 million annually with 50% growth in unit volume and over 20% growth in dollar volume. This growth is being largely prompted by the availability of the atmospheric pressure ionization techniques of electrospray and APCI. Significant enhancements in sensitivity that may be derived from counter-ion impingement electrospray, as well as reduction in effects from matrix suppression would have immediate application to the large existing commercial instrument market and to future markets.